There is a critical need in the pharmaceutical and other related industries to formulate industrially useful water-insoluble or poorly water soluble substances into formulations for oral, injectable, inhalation, ophthalmic, and other routes of delivery. Industrially useful water insoluble or poorly water soluble substances include water insoluble or poorly water soluble biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular water insoluble and poorly water soluble drugs for human and veterinary medicine.
No limitation is imposed on the kind of water-insoluble or poorly water soluble substances for use in the present invention. Examples include antipyretics, anti-inflammatories, analgesics, ataractics, sedatives, antitumor agents, antimicrobials, antibiotics, antilipemics, antitussives/expectorants, muscle relaxants, antiepileptics, antiulcers, antidepressants, antiallergics, cardiotonics, antiarrhythmics, vasodilators, hypotensors/diuretics, diabetes therapeutics, tuberculostatics, antirheumatics, steroids, narcotic antagonists, hormones, fat-soluble vitamins, anticoagulants, ischemic disease therapeutics, immune disease therapeutics, Alzheimer's disease therapeutics, osteoporosis therapeutics, angiopoiesis therapeutics, retinosis therapeutics, retinal vein occlusion therapeutics, senile disciform macular degeneration, cerebrovascular spasm therapeutics, cerebral thrombosis therapeutics, cerebral infarction therapeutics, cerebral occlusion therapeutics, intracerebral hemorrhage therapeutics, subarachnoid hemorrhage therapeutics, hypertensive encephalopathy therapeutics, transient cerebral ischemic attack therapeutics, multi-infarct dementia therapeutics, arterial sclerosis therapeutics, Huntington's disease therapeutics, brain tissue disorder therapeutics, optic neuropathy therapeutics, glaucoma therapeutics, ocular hypertension therapeutics, retinal detachment therapeutics, arthritis therapeutics, antisepsis drugs, antiseptic shock drugs, antiasthma drugs, pollakiuria/incontinentia therapeutics, atopic rhinitis therapeutics, allergic rhinitis therapeutics, cosmetic compositions, agrichemical compositions, insecticides, bactericides, herbicides, beverage or food compositions, immunosuppressants and animal drug compositions.
The fact that only water soluble substances can be administrated intravenously considerably impoverishes the assortment of organic molecules that can be used as antineoplastic drugs, as many if not most of these are poorly water soluble.
Incorporation of polar functions into such substances does not solve this problem because the changes of the structure lead to loss of the relevant pharmacological properties of the drugs.
Development of drug delivery systems which could enable dissolvation of poorly soluble compounds in aqueous solutions would be hugely instrumental in the efforts of realizing the anticancer potential of a vast number of substances, and would provide for creation of novel generations of drugs.
Paclitaxel and docetaxel belong to the taxane class of anticancer drugs because they or their precursors are produced by the plants of the genus Taxus (yews). Paclitaxel is still produced by isolation from natural sources while docetaxel, a semi-synthetic analogue of paclitaxel, is synthesized from 10-deacetyl baccatin. Paclitaxel differs from docetaxel by an acetylated hydroxyl function at position 10 and a benzoyl moiety instead of tert-butyl on the phenylpropionate side chain. The mechanism of action of taxanes is based on their ability to bind to the β subunit of tubulin which interferes with the depolymerization of microtubules, thereby damaging dividing cells. This specificity of action is widely used in oncology to treat different solid tumors, especially ovarian, lung, breast, bladder, head and neck cancer.
Paclitaxel and docetaxel have poor oral bioavailability and therefore intravenous (i.v.) infusion is the only way of administration. Scarce water solubility also makes it impossible to use aqueous solutions of these taxanes. Several delivery vehicles have been applied to solve this problem.
TAXOL® is based on the ability of CREMOPHOR® EL, a polyethoxylated castor oil, to dissolve paclitaxel in the weight-to-weight (w/w) ratio 87:1. It is chronologically the first commercial taxane formulation which has opened the era of taxane use in oncology. However it was later found that CREMOPHOR® is the cause of hypersensitivity reactions during TAXOL® infusion and for minimization of the incidence and severity of these reactions a premedication with histamine blockers and glucocorticoids as well as continuous infusion schedules became standard practice.
In a second delivery system called TAXOTERE®, Polysorbate 80 (known under the trademark TWEEN® 80), a derivative of polyethoxylated sorbitol and oleic acid, plays the role of vehicle. In this case the w/w ratio is 24:1. Like CREMOPHOR® EL, Polysorbate 80 is a non-ionic detergent build of polyethoxy chains and can also induce hypersensitivity reactions.
ABRAXANE®, a third delivery system, consists of paclitaxel nanoparticles stabilized by human serum albumin in the w/w ratio 9:1 with the mean diameter of nanoparticles being 130 nm. The absence of non-ionic surfactants simplifies the treatment as no premedication is necessary and the infusion time is shortened. On the other hand the ABRAXANE® formulation is less potent than TAXOL® because ABRAXANE® nanoparticles like other particles with the size more than 100 nm are a substrate for reticuloendothelial system. Another disadvantage of this drug delivery vehicle is that human serum albumin isolated from donor blood is used, which always carries a small but definite risk of transmission of viral diseases.
Finally, it has been found that paclitaxel and docetaxel can be dissolved in aqueous solutions of water-soluble derivatives of retinoic acid acting as anionic surfactants.
The uniqueness of the structure of these derivatives enables them to dissolve paclitaxel and docetaxel in the surprisingly low w/w ratio of 0.5:1.
Ixabepilone, (epothilone B analog) is very similar to taxanes in terms of mode of action and solubility in aqueous solutions. It is indicated for the treatment of metastatic or locally advanced breast cancer. Formulation of ixabepilone for IV administration, Ixempra, developed by BMS, like Taxol, is based on cremophor EL and therefore a premedication and prolonged infusion for the reducing of hypersensitivity reactions is required.
Etoposide, analog of toxin podophyllotoxin, is topoisomerase II inhibitor and is used for treatment of Ewing's sarcoma, lung cancer, testicular cancer, lymphoma and non-lymphocytic leukemia. Etoposide formulations for IV administration are based on PEG-derivatives such as Polysorbate 80 (TWEEN 80) or Macrogol 300 in order to solubilize the scarce water soluble active pharmaceutical ingredient.
Retinoids comprise a family of polyisoprenoids which includes vitamin A (retinol) and its natural (retinoic acid) and synthetic analogs (fenretinide, etretinate, tazarotene, bexarotene, adapalene). These compounds show a broad spectrum of biological activity including participation in control of cell proliferation, cell differentiation and embryonic development which enables to use retinoids as antineoplastic agents for treatment of different types of cancer such as leukemia, lymphoma, Kaposi's sarcoma, lung cancer and breast cancer. These compounds are also used for treatment of different skin disease like psoriasis, acne, and sun damaged skin. Retinoids are usually highly lipophilic compounds and their usage in form of aqueous solution demands application of some delivery system. However so far there are no any commercially developed water-soluble formulations of retinoids and they are available exclusively for oral administration.
Ciclosporin, sirolimus, tacrolimus, and everolimus are immunosuppressants which are scarcely water soluble. Bioavailability of the drugs at oral administration is only about 20%. Commercially available formulations of these immunosuppressants are based solely on the use of polyoxyethylated castor oil, which causes hypersensitivity reactions when intravenously administered.
Ciclosporin, cyclosporine, or cyclosporin, is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of a patient's immune system and so the risk of organ rejection. It has been studied in transplants of skin, heart, kidney, liver, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian soil sample, Ciclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids (an undecapeptide) produced by the fungus Tolypocladium inflatum Gams, and contains D-amino acids, which are rarely encountered in nature.
The search for and development of new drug delivery systems has increased with the realization of the fact that drugs in too high concentrations are toxic and—in best case—inactive in too low concentrations; however, exposing a cell to a too low concentrations of drugs often activates mechanisms of resistance to the drug. The range of concentrations where the drug elicits the desired response with less side-effects is known as “the therapeutic window”.
Prolonged infusions have been proven to reduce the toxicity of anticancer agents but this mode of administration is significantly more complicated from a practical point of view.
It has been found that slow drug release can be achieved by using drugs that are bound or encapsulated in nanoparticles of different kind. These particles can circulate in blood for several days playing the role of “depots”. The drug release occurs by diffusion of the encapsulated drugs or by erosion and decomposition of the particles. The most popular types of nanoparticles in this field of research are micelles and liposomes as the formation of such nanoparticles is a quite simple entropy driven process, i.e. they emerge spontaneously and their properties are programmed by conditions of the formation. The size of particles used in these delivery systems is within the range of 8 to 200 nm and even higher.
However, with the increase of the size, a particle becomes “visible” to the reticulo-endothelial system, a part of the immune system consisting of the phagocytic cells located in reticular connective tissue of lymph nodes, liver and spleen. The extent of reticulo-endothelial system clearance increases with the size of the particles, significantly reducing the total amount of the drug in the blood flow.
Another intriguing challenge in the field of drug delivery is the targeting of drugs to effect compartments which could increase the therapeutic effectiveness up to ultimate levels. Nanoparticles have been found very useful in this regard. Solid tumors differ pathoanatomically from healthy tissues by an extensive angiogenesis, as well as a hyperpermeable and defective vasculature architecture. In other words the size of the tumour capillaries is larger, making it potentially possible to significantly increase the passive transport of nanoparticles loaded with cytotoxic cargo to the tumour in comparison to a healthy endothelium.
US 2004048923 describes a group of retinoids including among numerous others the sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester and the sodium salt of N-(13-cis-retinoyl)-L-cysteic acid methyl ester. It is stated that the substances make it possible to manufacture new micelle formulations of poorly soluble pharmaceutical compounds like paclitaxel and docetaxel.
WO 02092600 relates to a method for preparing a water-soluble formulation of paclitaxel, comprising the steps of dissolving paclitaxel in a first solvent, dissolving a compound chosen among N-(all-trans-Retinoyl)-L-cysteic acid, N-(13-cis-Retinoyl)-L-cysteic acid, N-(all-trans-Retinoyl)-L-homocysteic acid, N-(13-cis-Retinoyl)-L-homocysteic acid, N-(all-trans-Retinoyl)-L-cysteinesulfinic acid, and N-(13-cis-Retinoyl)-L-cysteinesulfinic acid in a second solvent, mixing the aliquots of the resulting solutions of paclitaxel and the said compound in a desired molar ratio, and evaporating the resulting mixture to dryness.
Although the poor solubility of the pharmaceutical compounds may suggest that they are in particular form, US 2004048923 and WO 02092600 are both completely silent regarding the size and the morphology of the particles. There is in particular no indication or suggestion that they should be in amorphous state, or even that they could exist in such a state. Little less is any way of providing particles in such a state disclosed. As well known to those skilled in the polymorphism, including possible amorphism, is basically unpredictable for organic substances.